An emerging problem for societies in developed countries is extending years of healthy life. Specialists in biology and genetics argue that major breakthrough in the field can be achieved by revealing genetic variants which can be involved in regulation of phenotypes characterizing health, wellbeing and survival in late life. A puzzling problem is that phenotypes in late life are not the result of direct evolutionary selection that reinforces the role of the life course processes spahing genetic effects on health, wellbeing and survival within and across generations. Analysis of the role of the life course in genetic effects is not in mainstream of standard strategies of genome-wide association studies. The objective of this proposal is to identify systemic contribution of genetic and non-genetic factors to health, wellbeing, and survival over the life course by revealing associations of genetic factors with physiological and behavioral endophenotypes (EPs), by identifying their roles in risks of morbidity (cardiovascular disease (CVD) and cancer), disability, mortality, and mortality attributed to CVD and cancer, by elucidating the role of life-course related processes in shaping genetic effects on the risk outcomes, and by integrating the effects of genetic factors with the life course in men and women within and across generations. To achieve this goal, we will use rich data on individuals from different generations longitudinally followed in the Framingham Heart Study, Health and Retirement Study linked with Medicare data, the Coronary Artery Risk Development in Young Adults study, and the Long Life Family Study. The following Specific Aims will be addressed. Aim 1. Construction of phenotypes. Aim 2. Identification of genetic associations with EPs. Aim 3. Identification of genetic associations with risks of morbidity, disability, and mortality. Aim 4. Elucidating systemic role of the revealed genetic variants in health, wellbeing, and survival and conducting dynamic integration. Aim 5. Dissecting biological role of genes for the revealed SNPs.